On-resin Heck coupling enables small-molecule ligand discovery with covalent peptide-encoded libraries

Heck coupling remains challenging in solid-phase peptide synthesis (SPPS) and diversification of combinatorial small-molecule libraries. The intermolecular Heck reaction has not yet been implemented in SPPS, owing to the lack of effective catalysts achieving broad substrate scopes on resin-bound peptides. Peptide-encoded libraries (PELs) enable high-throughput identification of small-molecule ligands to protein targets and allow access to structurally diverse chemotypes. Here, we introduce a covalent PEL (coPEL) platform that incorporates on-resin Heck coupling to derivatize cysteine-reactive scaffolds during solid-phase library synthesis. We leverage the specific reactivity of palladium catalysts derived from tBuDavePhos to enable intermolecular on-resin Heck coupling reactions to rapidly diversify covalent acrylamide warheads. The optimized reaction conditions are high-yielding across a broad range of (hetero)aryl halides and acrylamides, ensuring robust performance and versatility within the coPEL platform. Screening a model coPEL against the epidermal growth factor receptor (EGFR) tyrosine kinase yielded original low-micromolar covalent inhibitors. This work establishes intermolecular on-resin Heck coupling as a practical tool for SPPS and expands the accessible chemical space for covalent ligand discovery.